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SOA Archives of Pharmacy & Pharmacology

Review Article Clinical Pharmacology of 5 Inhibitors in

This article was published in the following Scient Open Access Journal: SOA Archives of Pharmacy & Pharmacology Received September 20, 2018; Accepted October 01, 2018; Published October 08, 2018 Michel Bourin* Abstract Department of pharmacology, University of Nantes, 98, rue Joseph Blanchart 44100 Nantes, France The drugs active on erectile dysfunction in humans are now mainly phosphodiesterase 5 inhibitors, those that are marketed are , Vardefanil, Taladafil, and . We propose a synthesis of the pharmacological, pharmacokinetic and clinical properties of these derivatives. We have also listed their most common side effects and their potential drug interactions. Keywords: Phosphodiesterase 5 inhibitors, Sildenafil, Vardefanil, Taladafil, Avanafil.

Introduction Phosphodiesterase 5 (PDE 5) inhibitors are a type of targeted therapy used to treat people with pulmonary (PH) [1]. Targeted therapies slow the progression of PH and may even reverse some of the damage to the heart and . There are two

typesPDE of PDE5 inhibitors 5 inhibitor are currentlyalso used usedto treat to treat erectile PH: dysfunction sildenafil, [3]. This [2]. is because the body has the same type of cells in the blood vessels of the lungs as the blood vessels of

the penis. Viagra (sildenafil) has been used to treat erectile problems since 1998. to obtain or maintain an erection. These problems are common and can be solved effectivelyIn case byof erectileconsulting dysfunction a doctor itand is essential following to a determine suitable treatment. the cause ofUnless the difficulties there are

more serious causes of erectile dysfunction, the recommended treatment will usually be a PDE5 inhibitor. PDE5 inhibitors are a particularly effective type of drug treatment, minimallyWhat is ainvasive PDE5 (oral Inhibitor? dosage), with a low risk of side effects.

PDE 5 inhibitors block a particular (phosphodiesterase type 5), found in blood vessel walls [4]. PDE5 helps control blood flow to the pulmonary arteries. By stopping PDE5 from working, PDE 5 inhibitors (sildenafil and tadalafil) cause the blood vessels to relax. This increases blood flow to the lungs and lowers blood pressure. than 70% of patients with erectile dysfunction. These PDE5 inhibitors can be used to With PDE5 inhibitors, it is possible to restore the natural erectile response in more

treatSexual all types stimulation of impotence, stimulates regardless the ofrelease the cause of NO of the by disorder.the endothelium and non-

noradrenergic, non-cholinergic (NANC) parasympathetic fibers (rich in neuronal NOS) [5]. The NO diffuses cavernous bodies through the smooth fibers and binds to the hemic fraction of soluble , which stimulates cyclic GMP synthesis (cGMP). This cGMP is an important messenger in calcium signal transduction in the smooth fibers of cavernous bodies. CGMP reduces free sarcoplasmic calcium levels by binding to a cGMP-dependent protein kinase and a cGMP-dependent calcium channel [6]. This decrease in calcium promotes the relaxation of the smooth fibers of the arteries and cavernous bodies, allowing the expansion of sinusoidal spaces and erection. By inhibiting PDE5, the enzyme responsible for cGMP catabolism, sildenafil increases NO. *Corresponding Author: Michel Bourin, Department the absence of this stimulation [7]. of pharmacology, University of Nantes, 98, rue Since sexual stimulation is necessary to initiate NO release, sildenafil is ineffective in Joseph Blanchart 44100 Nantes, France, Email: PDE5 is the predominant isoform of phosphodiesterase in the of [email protected]

cavernous bodies. It is found in the smooth muscle fibers of other vessels especially

Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction

Page 2 of 6 pulmonary. The effects of PDE5 inhibition on pulmonary arterial hypertension are under study. The effects on asthma are rather compared with placebo, sildenafil doses of up to 100 mg resulted in a statistically significant increase in the duration of erections related to PDE4 inhibitors, which are involved in bronchial with a degree of rigidity of 60% (stiffness commonly considered Differentinflammation Drugs and contraction Used to ofTreat bronchial Erectile smooth Dysfunction muscle fibers sufficient for penetrating sex). In patients who responded to the drug, the median time between oral administration of 50 mg sildenafil and onset of erection (60% stiffness) in response to SSV The most commonly used PDE5 inhibitor drugs are sildenafil, was 25 minutes. The mean duration of erections with stiffness up to 60% at the base of the penis, in men who received placebo, 25 tovardenafil, achieve an tadalafil, erection andand maintain avanafil this [8]. erection These medicationswhen there mg and 50 mg sildenafil, in combination with a 2-hour exposure isthemselves sexual stimulation. do not produce PDE5 inhibitor erections tablets in men, have but no allow effect them in to SSV, was 3 minutes, 24 minutes and 32 minutes, respectively men with decreased libido and unable to produce a satisfactory [12,13]. erection. Sildenafil oralSildenafil administration is rapidly in fasted absorbed. subjects. Peak The plasma average concentration absolute is reached at 30 to 120 minutes (median: 60 minutes) after Sildenafil preferentially inhibits PDE5 and to a lesser extent bioavailability is 41% (range 25% to 63%). The pharmacokinetic PDE6 () [9] while it has no effect on PDE3 (heart). In vitro proportional when the dose is within the recommended dose parameters of sildenafil, when administered orally, are dose studies indicate that sildenafil is only 10-fold more selective for PDE5 than PDE6, while it is 4000 times more selective for PDE5 range (25 mg to 100 mg). Taking Sildenafil at a high-fat meal than PDE3. Sildenafil has no direct muscle relaxant effect on resulted in a marked slowing of the drug’s absorption rate, which isolated tissue of the human cavernous body. Rather, it enhances resulted in an average Tmax prolongation of 60 minutes and an the effect of NO by inhibiting PDE5, the enzyme responsible for average reduction of 29 minutes. % of Cmax [14]. In concrete biodegradation of cGMP in cavernous bodies. During the local terms, this means that if the patient takes his with a release of NO following sexual stimulation, the inhibition of PDE5 high-fat meal, the effect will be longer. Furthermore, even though by sildenafil produces an increase in the concentration of cGMP the amount of drug absorbed was lower (11% decrease in AUC), in the corpora cavernosa, hence the relaxation of the smooth and this decrease was statistically significant, it was not of clinical muscles they contain and the influx of blood into the penis [10]. absence of sexual stimulation. In vitro studies have shown that significance. The relative bioavailability of the product taken with Sildenafil given at the recommended doses has no effect in the a meal rather than fasting was 89% (90% CI, 84 to 94%) sildenafil has an affinity 10 to 10 000 times greater for PDE5 than The mean steady-state volume of distribution of Sildenafil for other phosphodiesterase’s (including PDE1, PDE2, PDE3, in(Vd the eq) circulation is 105 liters, both indicatingbind to plasma that theproteins product in approximately is distributed PDE4 and PDE6) and that it acts at least 700 times more on in the tissues. Sildenafil and its major N-desmethyl metabolite PDE5 than on PDE7 to 11. More precisely, the affinity of sildenafil for PDE5 is more than 4000 times higher than its affinity for the96%. sperm This ofparameter healthy volunteers is independent revealed of thatthe lesstotal than concentration 0.001% of PDE3, the cAMP-specific phosphodiesterase that participates at of the drug. Measurement of the amount of sildenafil present in the regulation of cardiac contractility. In addition, the effect of sildenafil is approximately 10 times more potent on PDE5 than the ingested dose may appear in the sperm of patients 90 minutes on PDE6, an isoenzyme found in the retina. This low affinity for after taking the drug. concentrationsPDE6 may explain of theabnormalities drug. in color discrimination observed Sildenafil is primarily removed from the body by two with high doses of sildenafil or in the presence of high plasma presentmicrosomal in the liver circulation isoenzymes, is formedCYP3A4 by (main N-demethylation metabolic pathway) of the and CYP2C9 (secondary metabolic pathway). The main metabolite PDE5 is also present in low levels in platelets, smooth vessels inhibitoryand viscera activity as well of nitric as in oxide skeletal on platelet muscles. aggregation The inhibition observed of actionN-methylpiperazine in vitro is equivalent part. The to approximately metabolite’s affinity 50% of for that PDEs of the is PDE5 by sildenafil in these tissues would explain the increased parentsimilar todrug. that Its of sildenafil,plasma concentration and the potency is about of its PDE540% inhibitoryof that of peripheral vasodilatation in vivo [11]. in vitro, inhibition of platelet thrombus formation in vivo and terminal half-life is approximately 4 hours. sildenafil. The N-demethyl derivative is also metabolized, and its

In eight placebo-controlled, double-blind, placebo-controlled devicetrials usingto objectively RigiScan® measure [RigiScan penile Ambulatory rigidity and Rigidity duration and of The total clearance of sildenafil is 41 L / h, and its terminal Tumescence Monitor, Dacomed Corp., Minneapolis, USA]) (a half-life is 3 to 5 hours. Sildenafil, administered orally or intravenously, is excreted as metabolites, mainly in the faeces placebo.erection), Some sildenafil participants is translated in these bytrials a markedhad established improvement organ dose)(approximately [15]. 80% of the administered dose) and, to a lesser in erections during sexual stimulation compared to taking extent, in the urine (approximately 13% of the administered dysfunction (spinal cord injury, , etc.), while others did not. In most of these trials, the efficacy of sildenafil was evaluated approximately 60 minutes after taking the product. In Studies on purified enzymatic preparations have shown all eight trials, when participants were subjected to visual-type that vardenafil is an inhibitor powerful and selective of PDE5 sexual stimulation (VSS), the results consistently showed that, in humans, its IC50 (concentration that inhibits 50% of the Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction

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nzymatic activity) being 0.7 nM. Vardenafil inhibits PDE5 more When the vardenafil film-coated tablet is taken with a high- than others known (effect> 15 times greater fat meal (containing 57% fat), the rate of absorption is decreased, than on PDE6 [present in the retina],> 130 greater than PDE1 with a median tmax elongation of 1 hour and an average Cmax [present in the brain, heart and vascular system]> 300 times decrease of 20%. The AUC of vardenafil is not modified. After larger than PDE11 [present in the testes, penile blood vessels, witha meal fasting containing administration. 30% fat, the absorption characteristics of smooth muscle of the vascular wall, skeletal muscles, prostate vardenafil (tmax, Cmax, and AUC) were unchanged compared and pituitary] and> 1000 times larger only on PDE2, 3, 4, 7, 8, 9 and 10). In vitro, vardenafil produces a rise in the concentration The mean steady-state volume of distribution of vardenafil erectionof CGMP thatin isolated depends human on the cavernous synthesis bodies, of monoxide resulting endogenous in muscle is 208 L, suggesting a tissue distribution. Vardenafil and its relaxation. At the conscious rabbit, vardenafil causes a penile main circulating metabolite (M1) are strongly bound to plasma proteins (approximately 95% for vardenafil or M1). For vardenafil nitrogen that is potentiated by donors [16]. as well as for M1, protein binding is independent of total drug In patients suffering from erectile dysfunction, erections concentrations. In healthy volunteers receiving vardenafil, less considered sufficient for penetration (rigidity of at least 60% than 0.00012% of the administered dose was in the ejaculate according to the RIGISCAN® device [RigiScan Ambulatory obtained 90 minutes after administration. primarily by hepatic metabolism via the Rigidity and Tumescent Monitor, Dacomed Corp., Minneapolis, Vardenafil, in the film-coated tablet form, is metabolised USA]) have been obtained by 64% of men treated with vardenafil 20 mg as soon as 15 minutes after taking, compared with 52% of isoform 3A4 (CYP) with the contribution of the CYP3A5 and men taking placebo [17]. The overall erectile response of subjects CYP2C isoforms. treated with vardenafil became statistically significant compared with placebo 25 minutes after dosing. In two RIGISCAN® double- plasmaIn humans, elimination the main half-life circulating is approximately metabolite (M1)4 hours. is produced Part of blind, placebo-controlled, and cross-over trials of men who had by N-desethylation of vardenafil and is then metabolized; its byhad visual erectile sexual dysfunction stimulation. for at Objectiveleast six months, measures the of10 stiffness mg and 20at mg doses of vardenafil significantly improved erections produced this metabolite M1 is found in glucuronoconjugate form in the systemic circulation. The selectivity profile of this M1 metabolite the base and end of the penis (with RIGISCAN®) during visual for phosphodiesterase’s is similar to that of vardenafil; in vitro, its sexual stimulation revealed that compared to placebo, vardenafil inhibitory power against phosphodiesterase type 5 is about 28% produced significantly better results at all doses and at all times. that of vardenafil, contributing about 7% to the effectiveness of The average duration of erection sufficient for penetration and the drug [21]. produced by visual sexual stimulation was 54 and 67 minutes In patients receiving vardenafil 10 mg orodispersible tablets, comparedat the base to of 31 the minutes penis and at the 39 base and of45 the minutes penis atand the 17 tip minutes of the the mean terminal half-life of vardenafil ranged from 4 to 6 hours. penis for the 10 mg and 20 mg doses of vardenafil, respectively, The elimination half-life of metabolite M1 is between 3 and 5 hours,Taladafil and is similar to that of vardenafil. at the tip of the penis for the placebo [18]. The chemical structure of PDE5 inhibitors is similar to that The shortest time between taking the drug and achieving an erection perceived to be sufficient for penetration and achieving full sexual intercourse was assessed in a double-blind, of cyclic guanosine monophosphate (cGMP). The structure of parallel-group and randomized distribution in men with erectile tadalafil is, however, very different from those of sildenafil and dysfunction. A higher proportion of men who took vardenafil 10 vardenafil, which are very similar. CGMP is a mediator of the mg or 20 mg than placebo reported full intercourse (p <0.025) regulation of several physiological processes, such as relaxation at all times after 10 minutes or more and 11 minutes or more, productionof smooth muscleproduces cells, the inhibition majority ofof platelet non-lytic aggregation physiological and adaptation of vision to brightness [22]. The increase in cGMP penetrationrespectively. and The achieving interval full between sexual takingintercourse the drugwas assessed (flexible dose) and achieving an erection perceived to be sufficient for effects of NO, including penile erection [23]. in a double-blind, parallel and randomized in men with erectile In addition to its high selectivity for PDE5, tadalafil has a dysfunction. A higher proportion of men who took vardenafil higher selectivity than sildenafil for PDE6, which may account for than those taking placebo reported having had complete sexual the greater number of vision problems with sildenafil. Another intercoursePharmacokinetics 8 to 10 hours after taking (p <0.001) [19]. example of different selectivity between these two molecules, but inverse, is relative to PDE11. PDE11 is the last of the isoforms to have been identified. It is present in many tissues such as the Vardenafil, in the form of a film-coated tablet, is rapidly heart, liver, kidneys, testes, brain and pituitary gland [24]. Today, absorbed. In some patients, peak plasma concentrations are the main benefit or risk related to the inhibition of this enzyme is reached just 15 minutes after oral administration. However, in 90% not known. None of the adverse events reported after more than inof cases,a fasted maximum subject. plasma The absolute concentrations oral bioavailability are obtained is within 15% 30on have4,000 therapeutic patients treated effects with only tadalafil, observed regardless at free concentrations of duration or to 120 minutes (median: 60 minutes) after oral administration greaterdosage, werethan relatedor equal to to its 10 inhibition. times the Tadalafil, concentration as well as required sildenafil, to average. After oral administration of vardenafil, the increase in AUC and Cmax is proportional to the dose over the recommended inhibit 50% of the enzyme activity (IC50) for PDE5 inhibition, range (5 to 20 mg) [20]. i.e. 10 nM. Even at the maximum concentration (Cmax) observed Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction

Page 4 of 6 fol on the ability of men with erectile dysfunction (ED) to achieve

lowing a single 20 mg dose of tadalafil in healthy volunteers, the free plasma concentration (74.4 nM) is 5-fold lower than the and maintain an erection sufficient for satisfactory sexual activity. IC50 for PDE11 . PDE inhibition is concentration-dependent and populationAvanafil was of evaluatedpatients with in 4 ED randomized, in patients double-blind,with diabetes placebo-mellitus isoform-dependentTwo studies in [24]. humans were conducted in which they controlled, parallel-group trials of up to 3 months in the general radical prostatectomy with bilateral nerve preservation. The type 1 or type 2 and DE, as well as in patients with ED following received 10 or 20 mg tadalafil daily for six months. There was no evidence of decreased or impaired concentration, motility, sexualfourth attempts study evaluated per patient the onsetthat resulted of action in ofsatisfactory avanafil for sexual two sperm morphology, or sperm volume under tadalafil at any dosages (100 and 200 mg), in terms of the proportion of dose. In addition, no effect was observed on the serum testicular or pituitary hormone levels required for sperm production, intercourse. A total of 1774 patients received avanafil, which irrespective of the dosage of tadalafil administered, for 6 months awas dose taken of the on demandstudy drug at 50about mg 30doses minutes (one study),before the100 onsetmg and of each day compared to placebo. The duration of 6 months shows that the effects of drugs leading to a decrease in sperm 200 mg (four studies), respectively. Patients were asked to take corresponding to 2 cycles of reproduction [25]. The literature to attempt sexual intercourse approximately 15 minutes after sexual activity. In the fourth study, patients were encouraged production in humans appear 4 to 8 weeks after the start of treatment and culminate at 4 months, which is less than the taking the product, to evaluate the occurrence of the erectogenic theevaluation results time.of a stress The clinical test showed cardiovascular that there tolerance was no statistically of tadalafil effect of avanafil, at the dosage of 100mg and 200mg on demand. has been specifically evaluated elsewhere [26]. In a recent trial, In addition, a subgroup of patients was included in an open- label extension study, in which 493 patients received avanafil significant difference between patients receiving tadalafil 10 for at least 6 months and 153 patients for at least 12 months. mg and those taking placebo on the time to cardiac ischemia mgPatients or decreased initially receivedto 50 mg a based 100 mg on dose their of individual avanafil and response could, toat occurrence[27]. Similarly, of myocardial administration infarction of 20 in mg the tadalafil population does included not affect in any time in the study, have their avanafil dose increased to 200 myocardial perfusion. Another notable point is the frequency of treatment. . In all studies, a statistically significant improvement the various studies. For patients treated with tadalafil, this rate was observed for all the main efficacy evaluation endpoints for is 0.28% during randomized double-blind studies and 0.43% for the Thesethree doses differences of avanafil were compared maintained to placebo during [30]. long-term age-adjustedopen-label studies, population. i.e. 0.39% in total. Comparatively, this rate is treatment (according to studies in the general population of 1.10% in all placebo-treated populations and 0.60 in the all-male Pharmacokinetics with ED following radical prostatectomy with bilateral nerve patients with ED, in patients with diabetes and ED, and in men

The time to obtain the Cmax after oral absorption is 2 thatpreservation, resulted in and successful in an open sexual extension intercourse study). was Inapproximately the general population of patients with ED, the average percentage of attempts pharmacologicallyhours; the Cmax iseffective. 74.4 μg This / l.point This is concentrationall the more important is much becausehigher, more it enables than tenrapid times, effective at the concentrations IC50, the assurance to be reached:of being 47%, 58%, and 59%, respectively, for the groups receiving 50 mg, percentage100 mg, and of200 successful mg of avanafil, sexual versus attempts about was28% approximatelyfor placebo. In a low concentration of tadalafil is sufficient to rapidly inhibit at men with either type 1 diabetes or type 2 diabetes, the average least 50% of the enzymatic activity, a minimum concentration to obtain a clinical effect [6]. In clinic, tadalafil is significantly 34% and 40%, respectively, for the 100 mg groups. and 200 mg effective from the 16th minute [28]. theavanafil, average versus percentage about 21% of for successful the placebo sexual group. attempts In men withwas ED following bilateral nerve-preserving radical prostatectomy, Elimination of tadalafil is relatively slow, with a half-life of 17 patientshours [26]. have It areflects satisfactory a good erection diffusion for in successful the tissues. penetration. The clinical approximately 23% and 26%, respectively, for the 100 mg and effectiveness of tadalafil may persist until 24 hours when 80% of 200 mg groups. avanafil, versus about 9% for placebo. In the (meanevaluation percentage study of of the successful onset of intercourseaction, avanafil per demonstratedpatient vs. time a In comparison, the time to obtain the maximum concentration statistically significant increase in the primary efficacy endpoint of sildenafil is one hour and its half-life is only 4 to 5 hours. The vardenafilAvanafil data are close to those of sildenafil. after dose - SEP3) versus placebo, having achieved satisfactory sexual intercourse in 24.71% of the attempts for the 100mg dose and 28.18% for the 200mg dose approximately 15 minutes after taking the product, versus 13.78% for the placebo. For all Avanafil is a reversible, highly selective and potent of the pivotal studies conducted with avanafil, the percentage of phosphodiesterase type 5 (PDE5) inhibitor specific for cyclic successful sexual attempts was significantly higher for all avanafil guanosine monophosphate (cGMP). When sexual stimulation doses compared with placebo, for all attempts at time intervals causes local release of nitric oxide, inhibition of PDE5 by avanafil studiedPharmacokinetics after taking the product [31]. results in an increase in cGMP in the corpora cavernosa of the penis. This results in slackening of the smooth muscles and an influx of blood into the penile tissues, thus producing an erection. Avanafil is rapidly absorbed after oral administration, with a Avanafil has no effect in the absence of sexual stimulation [28,29]. are proportional to all recommended dose ranges. It is essentially median Tmax of 30 to 45 minutes. Its pharmacokinetic properties In clinical studies, avanafil has been evaluated for its effect Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction

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perfectly combine this with PDE5 inhibitors. . The combination eliminated via hepatic metabolism (mainly by CYP3A4.) Avanafil ofat PDE5least 4inhibitors hours apart. with Usersnitrates who in alltake its cardiacforms is contraindicated can has a terminal half-life of approximately 6 to 17 hours, 5 to 0.75 hours after taking place on the occasion of a meal-rich meat; the rate of absorption is reduced, with an average delay to reach due to a risk of sudden . Association with enzyme Tmax of 1.25 hours and an average reduction of Cmax of 39% inhibitors, including antiproteases and antifungals, calcium (200 mg); significant effect on the intensity of exposure (AUC), channelReferences blockers is not recommended. minimal clinical significance [32]. 1. Channick R, Preston I, Klinger JR. Oral therapies for pulmonary arterial hypertension: endothelin receptor antagonists and phosphodiesterase-5 Avanafil is nearly 99% bound to plasma proteins. Protein inhibitors. Clin Chest Med. 2013;34(4):811-824. binding is independent of total active drug concentrations, age, 2. Wang RC, Jiang FM, Zheng QL, et al. Efficacy and Safety of Sildenafil and renal and hepatic function. No accumulation of avanafil in Treatment in Pulmonary Arterial Hypertension: a Systematic Review. Respir plasma was observed for 200 mg twice daily for 7 days. Based Med. 2014;108(3):513-517. administeredon measurements dose ofmay avanafil appear in in the the sperm sperm of of healthy patients. volunteers, 3. Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2013;381(9861):153- 45 to 90 minutes after its intake, less than 0.0002% of the 165.

4. Elhwuegi AS. The Wonders of Phosphodiesterase-5 Inhibitors: A Majestic Avanafil is eliminated mainly by the CYP3A4 (major route) History. Ann Med Health Sci Res. 2016;6(3):139-145. and CYP2C9 (first route) isoenzymes of hepatic microsomes. The 5. Mas M. Molecular mechanisms of penile erection. Arch Esp Urol. plasma concentrations of the major circulating metabolites, M4 2010;63(8):589-598. and M16, represent approximately 23% and 29%, respectively, of 6. Lasker GF, Pankey EA, Kadowitz PJ. Modulation of soluble guanylate the parent compound. The M4 metabolite has a phosphodiesterase cyclase for the treatment of erectile dysfunction. Physiology (Bethesda). selectivity profile similar to that of avanafil and in vitro inhibition 2013;28(4):262-269. potency for PDE5 equal to 18% compared to that of avanafil. 7. Hakky TS, Baumgarten AS, Parker J, et al. Penile rehabilitation: the Therefore, the M4 metabolite contributes about 4% of the total evolutionary concept in the management of erectile dysfunction. Curr Urol Rep. 2014;15(4):393. pharmacological activity. Metabolite M16 was inactive on PDE5 [29]. 8. Andersson KE. PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol. 2018;175(13):2554-2565.

Avanafil is highly metabolized in humans. After oral 9. Marmor MF, Kessler R. Sildenafil (Viagra) and ophthalmology. Surv administration, avanafil is excreted as metabolites mainly in the Ophthalmol. 1999;44:153-162. oralfeces dose). (approximately 63% of the administered oral dose) and to a 10. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an Orally Active Type 5 lesser extent in the urine (approximately 21% of the administered Cyclic GMP-Specific Phosphodiesterase Inhibitor for the Treatment of Penile Side effects of PDE5 Inhibitors Erectile Dysfunction. Int J Impote Res. 1996;8:47-52. 11. Wallis RM. The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. Nihon Yakurigaku Zasshi. 1999 ;114:22P-26P decreaseThe use gradually of PDE5 as inhibiting the body drugs,becomes like more any drug,familiar causes with side the effects. Most of the effects are usually mild or moderate and often 12. McCullough AR. Four-year review of sildenafil citrate. Rev Urol. active substances [33]. It is important to consider the side effects 2002;3:S26-S38. often help reduce side effects [34]. The table below lists the most 13. Hatzimouratidis K Sildenafil in the treatment of erectile dysfunction: an involved and find the right individual dosage. A milder dose will overview of the clinical evidence. Clin Interv Aging. 2006;1:403-414. (Table 1). 14. Akabane R, Sato T, Sakatani A, Miyagawa Y, Tazaki H, Takemura N. common side effects, based on a test of the listed tablet forms Pharmacokinetics of single-dose sildenafil administered orally in clinically healthy dogs: Effect of feeding and dose proportionality. J Vet Pharmacol Table 1: Common side effects of PDE5 inhibitors. Ther. 2018; 41:457-462.

Sildenafil Vardefanil Taladafil Avanafil 15. Kim EY, Lee SY, Jeon JY, et al. Pharmacokinetics of a new orally soluble 16% 16% 14% 15% film formulation of sildenafil administered without water. Int J Clin Pharmacol Nausea 7% 4% 10% 4% Ther. 2014;52(6):437-445. Back Pain - - 6% - 16. Saenz de Tejada I, Angulo J, Cuevas P, et al. The phosphodiesterase Nasal congestion 4% 10% 5% 10% inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil. Int J Impot Res. 2001;13:282-290. Muscle Pain - - 5% - Redness 10% 12% 4% 10% 17. Hellstrom WJ, Gittelman M, Karlin G, et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, Vision Disorder 3% - - - placebo-controlled trial. J Androl. 2002;23:763-771.

18. Hellstrom WJ, Gittelman M, Karlin G, et al. Sustained efficacy and tolerability Do PDE5 Inhibitors Interact with Certain Drugs? of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial. . 2003;61:8-14.

Although this type of drug is relatively harmless, it is important 19. Porst H, Rosen R, Padma-Nathan H, et al. The efficacy and tolerability of vardenafil, a new, oral, selective phosphodiesterase type 5 inhibitor, in treatmentto note that with PDE5 PDE5-inhibiting inhibitors are drugs not suitable is contraindicated for everyone. due For to patients with erectile dysfunction: the first at-home clinical trial. Int J Impot users who are also taking -containing medications, Res. 2001;13:192-199. 20. Heinig R, Weimann B, Dietrich H, Böttcher MF. Pharmacokinetics of a new an increased risk of falling blood pressure [35]. Ingesting alpha- blocker inhibitors and PDE5 inhibitors should be separated by Volume 1 • Issue 1 • 003 www.scientonline.org SOA Arch Pharm Pharmacol Citation: Michel Bourin (2018). Clinical Pharmacology of Phosphodiesterase 5 Inhibitors in Erectile Dysfunction

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orodispersible tablet formulation of vardenafil: results of three clinical trials. RE, Mitchell MI. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Clin Drug Investig. 2011;31:27-41 Pharmacol. 2006;61:280-288.

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